1. Field of the Invention
The present invention relates to a PPAR-activating compound able to selectively activate a peroxisome proliferator-activated receptor α (PPARα) from among peroxisome proliferator-activated receptors (PPAR), which is useful as a medicament.
2. Description of the Related Art
PPAR is known as one of nuclear receptor families and is hitherto known to have three subtypes (α, γ, and δ) (Nature, 347, 645-650, 1990; Cell, 68, pp 879-887, 1992; Cell, 97, pp 161-163, 1999; Biochim. Biophys. Acta., 1302, pp 93-109, 1996; and Journal of Medicinal Chemistry, 43, pp 527-550, 2000).
Of these subtypes, PPARα is mainly expressed in the liver and is shown to be activated by plasticizers and fibrate drugs, for example, Wy14643 and commercially available medicaments such as clofibrate, fenofibrate, bezafibrate, and gemfibrozil (Journal of the National Cancer Institute, 90, 1702-1709, 1998; and Current Opinion in Lipidology, 10, pp 245-257, 1999).
PPARα activation is known to accelerate fatty acid β-oxidation in mammals, leading to decrease triglyceride in the blood. In humans, PPARα activation decreases lipids in the blood such as low density lipoprotein (LDL) cholesterol and very low density lipoprotein (VLDL) cholesterol, and PPARα-activating drugs are useful as preventive or therapeutic agents for hyperlipidemia and so on. Moreover, the PPARα-activating drugs increase in high density lipoprotein (HDL) cholesterol and suppress the expression of VCAM-1, a cell adhesion molecule, in blood vessels, and as such, are also considered to be useful as preventive or therapeutic agents for arteriosclerosis and so on. Additionally, the PPARα-activating drugs are also considered to be useful in the prevention or treatment of diabetes and inflammatory diseases, in addition to cardiac diseases (Journal of Atherosclerosis and Thrombosis, 3, pp 81-89, 1996; Current Pharmaceutical Design, 3, pp 1-14, 1997; Current Opinion in Lipidology, 10, pp 151-159, 1999; Current Opinion in Lipidology, 10, pp 245-257, 1999; The Lancet, 354, pp 141-148, 1999; Journal of Medicinal Chemistry, 43, pp 527-550, 2000; and Journal of Cardiovascular Risk, 8, pp 195-201, 2001).
On the other hand, PPARγ is mainly expressed in adipocytes and is known to play an important role in the differentiation and proliferation of in adipocytes. Thiazolidine derivatives, for example, drugs such as troglitazone, pioglitazone, and rosiglitazone, are known as PPARγ activators. These drugs have been reported to improve insulin resistance by inducing smaller, highly insulin-sensitive in adipocytes to replace fully-differentiated adipocytes with reduced insulin sensitivity (Journal of Biological Chemistry, 270, 12953-12956, 1995; Endocrinology, 137, pp 4189-4195, 1996; Trends Endocrinol. Metab., 10, pp 9-13, 1999; and J. Clin. Invest., 101, pp 1354-1361, 1998). However, these drugs have also been reported to have unfavorable effects of causing weight gains and obesity attributed to increased fats in humans (The Lancet, 349, pp 952, 1997). Recent reports indicate that PPARγ antagonists are also likely to improve insulin resistance (Proc. Natl. Acad. Sci., 96, pp 6102-6106, 1999; The Journal of Biological Chemistry, 275, pp 1873-1877, 2000; and J. Clin. Invest., 108, 1001-1013, 2001).
Alternatively, PPARδ is ubiquitously present in body and has been reported to participate in lipid metabolism. However, there have been only a few reports about highly selective PPARδ activators, and the biological significance of PPARδ has remained unclear. Currently, the structures of PPARδ activators have been reported in many bibliographies (Diabetes, 46, 1319-1327, 1997; and Journal of Medicinal Chemistry, 43, pp 527-550, 2000). According to a recent report, GW501516, a PPARδ activator, elevates HDL levels in monkeys (Proc. Natl. Acad. Sci., 98, pp 5306-5311, 2001). Moreover, it has also been reported that activated PPARδ expressed in adipocytes or skeletal muscle cells promotes fat burning (Cell, 113, pp 159-170, 2003). Meanwhile, compound F disclosed as a PPARδ activator in WO 97/28149 has been reported to have unfavorable effects of promoting lipid accumulation in human macrophages (Journal of Biological Chemistry, 276, pp 44258-44265, 2001). In addition, experiments using PPARδ-deficient mice suggest that PPARδ activation contributes to lipid-accumulating effects (Proc. Natl. Acad. Sci., 99, pp 303-308, 2002). These phenomena are seen as mutually contradictory effects in the progression and treatment of arteriosclerosis. Accordingly, the therapeutic significance of PPARδ can be said to remain unclear.
From the viewpoint of the above, PPARα-selective activators that minimally activate PPARγ and PPARδ are expected to be useful in the prevention and treatment of hyperlipidemia, arteriosclerosis, diabetes, diabetes complications, inflammation, cardiac diseases, and soon, without weight gains and obesity.
Although some compounds activating PPARα have recently been reported (e.g., WO 02/046176, WO 04/000762, and WO 04/092130), these compounds cannot be said to be PPARα-selective. Under the present circumstances, there remains unfound about highly PPARα-selective compounds useful in the prevention or treatment of the diseases described above.